T-cell receptor diversity in minimal change disease in the NEPTUNE study,Pediatric Nephrology

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T-cell receptor diversity in minimal change disease in the NEPTUNE study
Pediatric Nephrology ( IF 2.6 ) Pub Date : 2022-08-09 , DOI: 10.1007/s00467-022-05696-x
Shiying Liu _{1,

2} , William S Bush _{1,

2,

3} , Kristy Miskimen _{1,

2,

3} , Agustin Gonzalez-Vicente ₄ , Jessica N Cooke Bailey _{1,

2} , Ioanna Konidari ₅ , Jacob L McCauley ₅ , John R Sedor ₄ , John F O'Toole ₄ , Dana C Crawford _{1,

2,

3}

Affiliation

Background

Minimal change disease (MCD) is the major cause of childhood idiopathic nephrotic syndrome, which is characterized by massive proteinuria and debilitating edema. Proteinuria in MCD is typically rapidly reversible with corticosteroid therapy, but relapses are common, and children often have many adverse events from the repeated courses of immunosuppressive therapy. The pathobiology of MCD remains poorly understood. Prior clinical observations suggest that abnormal T-cell function may play a central role in MCD pathogenesis. Based on these observations, we hypothesized that T-cell responses to specific exposures or antigens lead to a clonal expansion of T-cell subsets, a restriction in the T-cell repertoire, and an elaboration of specific circulating factors that trigger disease onset and relapses.

Methods

To test these hypotheses, we sequenced T-cell receptors in fourteen MCD, four focal segmental glomerulosclerosis (FSGS), and four membranous nephropathy (MN) patients with clinical data and blood samples drawn during active disease and during remission collected by the Nephrotic Syndrome Study Network (NEPTUNE). We calculated several T-cell receptor diversity metrics to assess possible differences between active disease and remission states in paired samples.

Results

Median productive clonality did not differ between MCD active disease (0.0083; range: 0.0042, 0.0397) and remission (0.0088; range: 0.0038, 0.0369). We did not identify dominant clonotypes in MCD active disease, and few clonotypes were shared with FSGS and MN patients.

Conclusions

While these data do not support an obvious role of the adaptive immune system T-cells in MCD pathogenesis, further study is warranted given the limited sample size.

Graphical abstract

A higher resolution version of the Graphical abstract is available as Supplementary information.

中文翻译：

NEPTUNE 研究中微小病变的 T 细胞受体多样性

背景

微小病变肾病 (MCD) 是儿童特发性肾病综合征的主要原因，其特征是大量蛋白尿和使人虚弱的水肿。MCD 中的蛋白尿通常可通过皮质类固醇治疗迅速逆转，但复发很常见，并且儿童经常因免疫抑制治疗的重复疗程而出现许多不良事件。MCD 的病理生物学仍然知之甚少。先前的临床观察表明，异常的 T 细胞功能可能在 MCD 发病机制中发挥核心作用。基于这些观察结果，我们假设 T 细胞对特定暴露或抗原的反应会导致 T 细胞亚群的克隆扩增、T 细胞库的限制以及引发疾病发作和复发的特定循环因子的详细说明.

方法

为了验证这些假设，我们对 14 名 MCD、4 名局灶性节段性肾小球硬化 (FSGS) 和 4 名膜性肾病 (MN) 患者的 T 细胞受体进行了测序，这些患者具有肾病综合征研究在疾病活动期间和缓解期间采集的临床数据和血液样本网络（海王星）。我们计算了几个 T 细胞受体多样性指标，以评估配对样本中活动性疾病和缓解状态之间的可能差异。